Psoriasis is a systemic inflammatory skin disease mediated by the innate and adaptive immune systems. Recent studies have indicated that macrophages may contribute to the pathogenesis of psoriasis. However, the role of macrophage protein geranylgeranyl transferase type-1β subunit (PGGT1B) in psoriasis is unclear. In this study, we aimed to establish how a reduction in Pggt1b expression in monocytes influences the onset and progression of psoriasis.

Myeloid cell-specific Pggt1b knockout mice were generated, and their bone marrow-derived macrophages (BMDMs) were stimulated with resiquimod (R848) to mimic the psoriatic immune microenvironment. The proteomic analysis enabled us to identify 17 differentially expressed proteins associated with Pggt1b deficiency in the psoriasis macrophage model (folded change ≥ 1.3 and p < 0.05). Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment was performed. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and western blot assays were used to verify the differentially expressed proteins and signaling pathways. Finally, an enzyme-linked immunosorbent assay was used to verify the expression of the key inflammatory cytokine interleukin (IL)-1β.

In total, six proteins (Dlgap5, Fas, Fnta, Nlrp3, Cd14, and Ticam2) were identified as hub proteins. Furthermore, we found that Pggt1b might mediate R848-induced inflammation via the small G-proteins Rac1 or Cdc42. We found that Pggt1b positively regulates pro-inflammatory responses in R848-stimulated BMDMs via the NF-κB signaling pathway.

This study clarified that PGGT1B affected the synthesis of inflammatory cytokines via NF-κB pathway and provided insights into the mechanisms underlying immune responses and inflammation.

Psoriasis is a chronic inflammatory skin disease characterized by dysregulation of the interleukin 17 (IL-17) signaling axis. Given that psoriasis development depends on keratinocyte stem cells and early progenitors' sensitivity to differentiation, we analyzed IL-17 ligands and the expression and function of in a novel subset of keratinocyte subpopulations: keratinocyte stem cells (KSC) and early and late Transit Amplifying (ETA or LTA, respectively) cells. We found that all subpopulations expressed all IL-17 variants, predominantly in ETA and LTA. Conversely, IL-17 receptor expression resulted in more heterogeneity, with IL-17RA, -C, and -E being the most differentially regulated. Stimulus with IL-17A, IL-17-F, IL-17-A/F, and IL-17C promotes the upregulation of CXCL1, CXCL8, and DEFB4 mRNAs expression in both KSC and ETA. Moreover, IL-17A and IL-17A/F mainly decrease KSC proliferation and promote cell cycle block. Globally, IL-17A and IL-17A/F modulated the expression of proliferation, differentiation, and psoriasis-associated markers. Furthermore, KSC- and ETA-derived 3D reconstructions displayed increased epidermal thickness and upregulated KRT16 expression after treatment with IL-17A or IL-17A/F. Therefore, our data demonstrated that IL-17 family members perform distinctive functions in a specific keratinocyte subpopulation and define IL-17 signaling as a critical modulator of KSC behavior, proving its role in epidermal homeostasis dysregulation of psoriasis.

Hidradenitis suppurativa (HS) is a chronic relapsing inflammatory skin disease associated with significant comorbidities and poor quality of life. Despite uncertainty about pathways driving inflammation in HS lesions, the cytokines interleukin (IL)-17A and IL-17F have been shown to be upregulated in patients with HS. Previous studies have demonstrated that the monoclonal IgG1 antibody bimekizumab selectively inhibits IL-17F in addition to IL-17A.

To further investigate the roles of IL-17A and IL-17F in HS pathogenesis.

RNA sequencing (RNAseq) was conducted on skin biopsies taken at baseline and after treatment at week 12 of a phase II proof-of-concept study of bimekizumab in patients with moderate-to-severe HS. Differentially expressed genes were identified between baseline lesional and nonlesional samples and between lesional samples before and after bimekizumab treatment, to describe molecular disease mechanisms and treatment effect. Human hair follicular keratinocytes (HHFK) were cultured and treated with a supernatant of stimulated T helper (Th)17 cells in combination with anti-IL-17A, anti-IL-17F, anti-IL-17A and anti-IL-17F, or IgG control antibodies. Total mRNA was analysed by RNAseq. Cellular supernatants from the stimulated HHFKs were used as a source of Th17-induced chemoattractants in neutrophil chemotaxis assays.

RNAseq revealed that the most prominently upregulated genes in HS lesions included those associated with neutrophil biology. Bimekizumab treatment resulted in reduced expression of these genes. The extent of reduction in gene expression was dependent on achieving HiSCR50 (≥ 50% reduction from baseline in the total abscess and inflammatory nodule count, with no increase from baseline in abscess or draining tunnel count). In vitro dual inhibition of IL-17A and IL-17F had greater attenuation of Th17-induced HS-associated genes and neutrophil migration in HHFKs vs. IL-17A or IL-17F inhibition alone. In situ hybridization found that IL-17A- and IL-17F-producing cells in HS lesions can lack the IL-23 receptor and IL-1β could induce IL-23-independent IL-17F expression in vitro. Furthermore, mucosal-associated invariant cells in HS tunnels expressed IL-17F and IL-1 receptor type 1. IL-1β-, IL-17A- and IL-17F-expressing cells were found to be co-localized in HS lesions.

These data support the hypothesis that IL-17A and IL-17F play central roles in HS, a neutrophilic dermatosis. The presence of IL-1β may partly explain the high expression of IL-17F in lesional HS tissue.

Psoriasis, a chronic inflammatory systemic disease, may increase the risk of allergic diseases. This meta-analysis assesses the prevalence and risk of developing allergic rhinitis in psoriasis. We systematically searched MEDLINE, Scopus, and EMBASE for population-based studies documenting AR in psoriasis compared to those without from inception to December 2023. Meta-analysis was conducted using the random-effects model. Eight studies, comprising 5 cross-sectional studies, 1 case-control study, 1 retrospective cohort study, and 1 prospective cohort study, were included. The increased prevalence of AR was 22.29% (95% CI: 0.135 to 0.281; P < 0.001; I2 = 99.05%) in the psoriasis population. The AR risk in psoriasis was insignificant (adjusted OR 1.19%; 95% CI: 0.69 to 2.06; I2 = 99%; P < 0.00001). Subgroup analysis in moderate to severe psoriasis cases revealed a trend of higher risk of AR (OR 1.41%; 95% CI: 0.94 to 2.10; I2 = 92%; P = 0.0003) with very low certainty of evidence. High heterogeneity was observed in most analyses. Our meta-analysis demonstrated a higher prevalence of AR in psoriasis patients. Evaluating and treating allergic diseases can enhance holistic treatment.

Among all malignancies, colorectal cancer ranks third in incidence rate and second in mortality rate. Human beta-defensin-1 (hBD-1) has broad-spectrum antimicrobial properties, and it plays an important role in the tumor microenvironment. Circular ribonucleic acids (circRNAs) regulate the proliferation and progression of colorectal cancer cells via cancer-related signaling pathways.

Cell proliferation was assessed using the Cell Counting Kit-8 assay to determine the optimal hBD-1 concentration. Intracellular autophagic vesicles were visualized via monodansylcadaverine staining. In addition, the levels of AKT and mammalian target of rapamycin (mTOR)-associated signaling proteins were analyzed via Western blot analysis. CircRNA microarrays and quantitative real-time polymerase chain reaction were used to identify differentially expressed circRNAs in colon cancer cell lines. The functional role of HAS-CIRCpedia-5280 in vitro was demonstrated by overexpressing HAS-CIRCpedia-5280 and inhibiting miR-4712-5p. HAS-CIRCpedia-5280 could be a sponge of miR-4712-5p, mimicking the effect induced by HAS-CIRCpedia-5280 overexpression in colon cancer cells.

hBD-1 inhibited the proliferation of colon cancer cells and increased the number of intracellular autophagic vesicles. In addition, hBD-1 inhibited the AKT/mTOR signaling pathway, thereby enhancing cellular autophagy. Further, the interaction of HAS-CIRCpedia-5280 and miR-4712-5p was investigated. hBD-1 upregulated the expression level of HAS-CIRCpedia-5280 and downregulated the expression level of miR-4712-5p in colon cancer cells. Subsequently, the overexpression of HAS-CIRCpedia-5280 or the inhibition of miR-4712-5p activated the AKT/mTOR signaling pathway, leading to cellular autophagy inhibition. Conversely, the mimicry of miR-4712-p counteracted the effect of HAS-CIRCpedia 5280 overexpression in colon cancer cells by inhibiting the activation of the AKT/mTOR signaling pathway and, thereby, enhancing cellular autophagy.

hBD-1 can have an inhibitory effect against cell proliferation in colon cancer SW-620/HCT-116 cells via the HAS-CIRCpedia-5280/miR-4712-5p-mediated activation of autophagy.

T-helper 17 (Th17) cells produce homodimeric IL17A/A and IL17F/F cytokines as well as the heterodimeric IL17A/F isoform, all having well known roles in defense against extracellular pathogens including fungal infection. Antibodies targeting IL17A (such as secukinumab and ixekizumab) have been approved to treat psoriasis, psoriatic arthritis, ankylosing spondylitis, and axial spondyloarthritis and are under further investigation as therapies in inflammatory disorders such as hidradenitis suppurativa and giant cell arteritis. Because many patients dislike injections with needles, orally bioavailable small molecule IL17 antagonists are desirable as next-generation drugs as long as they can replicate the degree of efficacy observed with anti-IL17A biologics. We recently described novel small molecules binding as 2 copies to the IL17A/A homodimer with only weak effects on the IL17A/F heterodimer. Because approved antibodies binding IL17A neutralize both IL17A/A and IL17A/F, we assessed whether targeting IL17A/A would be sufficient to bring efficacy comparable to IL17A biologics. In comparison to IL17A/F and IL17F/F, we found that the IL17A/A homodimer is the strongest initiator of signaling and that comparable IL17A/A to IL17A/F ratios are expressed in Th17 cells and in human psoriatic skin tissue. Furthermore, our IL17A/A-specific small molecules block the effects of Th17 cell supernatants on keratinocytes to similar maximal responses as anti-IL17A. Our IL17A/A-selective antagonists deliver comparable efficacy to anti-IL17A biologics in several rodent inflammatory models of psoriasiform dermatitis and arthritis. These results support neutralizing IL17A/A with oral small molecule antagonists is an attractive approach to provide differentiated, next-generation therapies for inflammatory disorders. SIGNIFICANCE STATEMENT: This study found that orally active small molecule antagonists of the proinflammatory cytokine IL17A that preferentially bind the IL17A/A form produced equivalent efficacy to monoclonal antibodies that can neutralize both IL17A/A and IL17A/F. This indicates that the IL17A/A homodimer is the dominant isoform driving inflammation in diseases such as psoriasis and that oral inhibitors targeting IL17A/A may be useful next-generation IL17 therapeutics.

Psoriasis, a widespread and chronic inflammatory skin disorder, is marked by its persistence and the lack of a definitive cure. The pathogenesis of psoriasis is increasingly understood, with ongoing research highlighting the intricate interplay of genetic, immunological, and environmental factors. Recent advancements have illuminated the pivotal role of microRNAs in orchestrating complex processes in psoriasis and other hyperproliferative skin diseases. This narrative review highlights the emerging significance of miRNAs as key regulators in psoriasis pathogenesis and examines their potential as therapeutic targets. We discuss current treatment approaches and the promising future of miRNAs as next-generation therapeutic agents for this condition.

Psoriasis risk can be affected by exposure to mixtures of environmental chemicals; however, the effect of brominated flame retardants (BFRs) exposure on self-reported psoriasis has not been assessed. Herein, we evaluated the association between the exposure to BFRs compounds of 6 chemicals with risk of psoriasis. Based on data from the National Health and Nutrition Examination Survey (NHANES) 2003-2006 and 2009-2014, this analysis was conducted among 6340 adults. Multivariable logistic regression, restricted cubic splines (RCS), weighted quantile sum (WQS) regression, quantile-based g computation (Qgcomp) regression, and Bayesian kernel machine regression (BKMR) models were performed to estimate the associations. Our results indicated that co-exposure to BFRs was associated with increased risk of psoriasis. Notably, PBB153 emerged as a significant factor contributing to the risk of psoriasis, and showed a non-linear relationship between the concentration of serum PBB153 and the prevalence of psoriasis. Moreover, the association between PBB153 and psoriasis risk remained stable across all subgroup analyses, including those stratified by gender. Our study presents robust evidence connecting BFRs exposure to the prevalence of psoriasis, emphasizing the necessity for continued research and policy interventions to address this environmental health issue. Because BFRs are extensively used and detected in various environmental sources and living organisms, future investigations should further elucidate the mechanisms underlying the observed associations between BFRs exposure and psoriasis risk.

Psoriasis is a chronic, immune-mediated disease. The systemic inflammation triggered by psoriasis contributes significantly to increased cardiovascular risk. While various treatments completely clear the skin, the associated effects on systemic inflammation are not yet clear. We investigated residual systemic inflammation in successfully treated patients. Circulating disease-specific and non-specific inflammatory markers were measured and compared in 80 psoriasis patients (aged 30-45 years) successfully treated with topical therapy, methotrexate, adalimumab, secukinumab or guselkumab, and in 20 healthy controls. Non-specific inflammatory markers (high-sensitivity C-reactive protein (hs-CRP), complete blood count (CBC) parameters, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), mean platelet volume-to-platelet ratio (MPR), and red blood cell distribution width-to-platelet ratio (RPR)) and disease-specific inflammatory markers (interferon-γ (IFN-γ), tumor necrosis factor (TNF), interleukin (IL)-1β, IL-12p70, IL-17, and IL-23) were measured and compared between groups. Disease-specific cytokines (IFN-γ, TNF, IL-1β, IL-12p70, and IL-17, but not IL-23), were significantly elevated in patients compared to controls, while non-specific inflammatory markers showed no differences compared to controls. The residual disease-specific cytokines were similarly elevated in all five treated groups. In addition, they correlated significantly with body mass index (BMI) and waist circumference. Our results suggest that psoriasis patients have elevated residual disease-specific cytokines despite successful treatment, while the non-specific inflammatory markers are similar to those in control subjects. Residual disease-specific inflammatory markers correlated with BMI and waist circumference. A possible beneficial effect of body weight control in psoriasis patients merits further investigation. The study was registered at http://clinicaltrials.gov (identifier: NCT05957120) on July 24, 2023.

A persistent long-standing, inflammatory skin condition that is brought on by a variety of factors is psoriasis. It is distinguished by itchy, scaly, reddish plaques, particularly on areas of the body that are frequently chafed, including the extensor sites of the limbs. Recent developments in molecular-targeted therapy that use biologics or small-molecule inhibitors can effectively cure even the worst psoriatic indications. The outstanding clinical outcomes of treatment help to clarify the disease's detrimental consequences on quality of life. Biomarkers that identify deep remission are essential for developing uniform treatment plans. Blood protein markers such as AMPs that are consistently quantifiable can be very helpful in routine clinical practice. The metabolic pathways involve biomarkers that can not only help diagnose psoriasis in a clinical setting but also indicate its severity based on the levels present in the body. Machine learning and AI have made a diagnosis of the expression of genes as biomarkers more accessible. In this article, biomarkers, as well as their key role in psoriasis, are discussed.

In recent years, cancer immunotherapy has introduced novel treatments, such as monoclonal antibodies, which have facilitated targeted therapies against tumor cells. Programmed death-1 (PD-1) is an immune checkpoint expressed in T cells that regulates the immune system's activity to prevent over-activation and tissue damage caused by inflammation. However, PD-1 is also expressed in tumor cells and functions as an immune evasion mechanism, making it a therapeutic target to enhance the immune response and eliminate tumor cells. Consequently, immune checkpoint inhibitors (ICIs) have emerged as an option for certain tumor types. Nevertheless, blocking immune checkpoints can lead to immune-related adverse events (irAEs), such as psoriasis and cytokine release syndrome (CRS), as exemplified in the clinical case presented by Zhou et al involving a patient with advanced gastric cancer who received sintilimab, a monoclonal antibody targeting PD-1. Subsequently, the patient experienced exacerbation of psoriasis and CRS. The objective of this editorial article is to elucidate potential immunologic mechanisms that may contribute to the development of CRS and psoriasis in patients receiving ICIs. It is crucial to acknowledge that while ICIs offer superior safety and efficacy compared to conventional therapies, they can also manifest irAEs affecting the skin, gastrointestinal tract, or respiratory system. In severe cases, these irAEs can lead to life-threatening complications such as circulatory shock or multiorgan failure. Consequently, it is recommended that patients receiving ICIs undergo regular monitoring to identify and manage these adverse events effectively.

The growing evidence of chronic inflammation and sequelae caused by psoriasis indicates the need for systemic treatment, including biologics and conventional treatments like methotrexate. However, unconscious racial bias may lead to discrepancies in systemic medication prescription. Racial identity is also suspected to affect comorbidity and hospitalization rates in patients with psoriasis. This study examines the impact of race on hospitalization duration and systemic medication prescription patterns in patients with psoriasis in the United States in 2020. The 2020 Healthcare Cost and Utilization (HCUP) National Inpatient Sample (NIS) database was used, with inpatient admissions over the age of 17 with an ICD-10-coded psoriasis diagnosis included. Patient demographics and hospital characteristics were compared between "non-white" and "white" patients, with white patients as the reference group. The primary outcome, systemic medication prescription, was evaluated using logistic regression models, producing an odds ratio and corresponding 95% confidence interval (CI). The secondary outcome, length of stay, was evaluated using negative binomial regression models to approximate the incident rate ratio and 95% CI. 1,802,720 patients with psoriasis were included in this study. Hispanic, Asian or Pacific Islander, and Native American patients with psoriasis had significantly lower odds of systemic medication prescription than white patients with psoriasis. All non-white racial identities were found to have significantly longer estimated lengths of stay compared to white patients with psoriasis. Disparities in the medication of choice for psoriasis treatment can lead to increased inpatient burden with longer lengths of stay for non-white patients.

Psoriasis is a complex, chronic inflammatory skin disease that significantly impacts patients' quality of life (QOL), especially in cases of genital, nail, and scalp psoriasis. Bimekizumab is an inhibitor of interleukin (IL)-17A and IL-17F and used for the treatment of psoriasis. The aim of this retrospective study was to evaluate the effectiveness of bimekizumab through in treating genital, nail, and scalp lesions with psoriasis over 24 weeks. The study was conducted from May 2022 and February 2024 on 52 psoriasis patients treated with bimekizumab. The therapeutic effects of bimekizumab were evaluated by the achievement of Physician's Global Assessment (PGA) rates of 0/1 on the genitals (genital-PGA), fingernails (PGA-F), scalp-specific PGA (ss-PGA), static PGA (sPGA), and the Dermatology Life Quality Index (DLQI) at weeks 4, 16, and 24. Bimekizumab treatment significantly improved genital, nail, and scalp lesions with psoriasis. At week 24, the achievement rate of genital-PGA 0/1, PGA-F 0/1, ss-PGA 0/1 was 96.2%, 66.7%, or 93.9%, and that of sPGA 0/1 or DLQI 0/1 was 93.9% or 83.3%, respectively. Bimekizumab was effective for genital, nail, and scalp lesions with psoriasis, difficult-to-treat lesions, and simultaneously improved QOL in a real-world clinical practice.

Vascular endothelial growth factor A (VEGF-A)-mediated angiogenesis is involved in the pathogenesis of psoriasis. VEGF-A inhibitors are widely used to treat oncological and ophthalmological diseases but have not been used in psoriasis management. The molecular mechanisms underlying the effects of VEGF-A inhibition in psoriatic skin remain unknown.

To identify the genes and canonical pathways affected by VEGF-A inhibition in non-lesional and plaque skin ex vivo.

Total RNA sequencing was performed on skin biopsies from patients with psoriasis (n = 6; plaque and non-lesional skin) and healthy controls (n = 6) incubated with anti-VEGF-A monoclonal antibody (bevacizumab, Avastin®) or human IgG1 isotype control for 12 h in serum-free organ culture. Differentially expressed genes between paired control and treated samples with adjusted p-values <0.1 were considered significant. Gene ontology and ingenuity pathway analysis was used to identify enriched biological processes, canonical pathways and upstream regulators.

VEGF-A inhibition upregulated the expression of genes involved in lipid metabolism. Pathway enrichment analysis identified the activation of pathways involved in fatty acids and lipid biosynthesis and degradation in non-lesional skin and ferroptosis in plaque skin. VEGF-A inhibition downregulated endothelial cell apoptosis in non-lesional psoriasis skin and members of the interferon family were identified as potential regulators of the effects of VEGF-A inhibition in non-lesional skin.

Early response to VEGF-A inhibition is associated with changes in lipid metabolism in non-lesional psoriasis skin and cellular stress in psoriasis plaque. More investigation is needed to validate these findings.

Psoriasis is a prevalent, inflammatory skin disease without cure. Further research is required to unravel dysregulated processes and develop new therapeutic interventions. The lack of suitable in vivo and in vitro preclinical models is an impediment in the psoriasis research. Recently, the development of 3D skin models has progressed including replicas with disease-like features. To investigate the use of in vitro models as preclinical test tools, the study focused on treatment responses of 3D skin replicas. Cytokine-priming of skin organoids induced psoriatic features like inflammation, antimicrobial peptides (AMP), hyperproliferation and impaired differentiation. Topical application of dexamethasone (DEX) or celastrol (CEL), a natural anti-inflammatory compound reduced the secretion of pro-inflammatory cytokines. DEX and CEL decreased the gene expression of inflammatory mediators. DEX barely affected the psoriatic AMP transcription but CEL downregulated psoriasis-driven AMP genes. Subcutaneous application of adalimumab (ADM) or bimekizumab (BMM) showed anti-psoriatic effects via protein induction of the differentiation marker keratin-10. Dual blockage of TNF-α and IL-17A repressed the inflammatory psoriasis phenotype. BMM inhibited the psoriatic expression of AMP genes and induced KRT10 and cell-cell contact genes. The present in vitro model provides a 3D environment with in vivo-like cutaneous responses and represents a promising tool for preclinical investigations.

The human skin forms a dynamic barrier to physical injuries and microbial invasion. Constant interactions between stroma and tissue-confined immune cells maintain skin homeostasis. However, the cellular interactions that maintain skin health also contribute to focal immunopathology. Psoriasis is a common disease that manifests with focal pathology induced by environmental triggers in genetically susceptible individuals. Within psoriasis plaques, cross-talk between skin-resident T cells and stroma cells leads to chronic inflammation. Inflammatory cytokines such as TNF-α, IL-17, IL-22, and IL-23 amplify the local chronic inflammation and sustain the well-demarcated thick and scaly plaques that characterize the disease. In resolved lesions, T cells remain poised for IL-17 and IL-22 production, and postinflammatory epigenetic modifications lower the threshold for initiation of local relapse. This review focuses on how tissue-resident memory T cells contribute to the onset, maintenance, resolution, and relapse of psoriasis.

This study was performed to explore the clinical significance of the expression of human beta-defensin 2 (HBD-2) and chemokine ligand 1/2 (CXCL-1/2) in psoriasis vulgaris.

This study retrospectively included the study group (n = 160) and control group (n = 100) for analysis. The levels of inflammatory indicators, blood biochemical indicators, and immune indicators using ELISA. The psoriasis area and severity index (PASI) was used to evaluate disease severity. Levels of HBD-2, CXCL-1, CXCL-2 and CCL20 were determined by RT-PCR. The correlations of HBD-2, CXCL-1 and CXCL-2 levels with CCL20 and PASI scores were analyzed. The diagnostic value of HBD-2, CXCL-1 and CXCL-2 in psoriasis vulgaris was analyzed by ROC curve.

HBD-2, CXCL-1 and CXCL-2 were highly expressed in the lesions of psoriasis vulgaris patients, and were positively correlated with CCL20 and PASI score. HBD-2, CXCL-1 and CXCL-2 alone or in combination had high diagnostic value for psoriasis vulgaris and severe psoriasis, and the combined diagnostic value of the three was higher than that of a single indicator.

HBD-2, CXCL-1, and CXCL-2 levels are closely related to the severity of psoriasis vulgaris and can effectively diagnose the occurrence and progression of psoriasis vulgaris.

(1) Background/Objectives: Nail psoriasis (NP) is a chronic and difficult-to-treat disease, which causes significant social stigma and impairs the patients' quality of life. Moreover, nail psoriasis is a true therapeutic challenge for clinicians. The presence of nail psoriasis can be part of a severe form of psoriasis and can have predictive value for the development of psoriatic arthritis. Our real-world-evidence multicenter study aims to evaluate the efficacy of bimekizumab in nail psoriasis. (2) Methods: A retrospective analysis of a multicenter observational study included 834 patients affected by moderate-to-severe psoriasis, in 33 Dermatologic Units in Italy, treated with bimekizumab from December 2022 to September 2023. Clinimetric assessments were based on Psoriasis Area and Severity Index (PASI), Dermatology Life Quality Index (DLQI), and Physician's Global Assessment of Fingernail Psoriasis (PGA-F) for the severity of nail psoriasis at 0, 12, 24, and 36 weeks. (3) Results: Psoriatic nail involvement was present in 27.95% of patients. The percentage of patients who achieved a complete clearance of NP in terms of PGA-F 0 was 31.7%, 57%, and 88.5% at week 4, 16, and 36, respectively. PASI 100 was achieved by 32.03% of patients at week 4, by 61.8% at week 16, and by 78.92% of patients at week 36. The mean baseline PASI was 16.24. The mean DLQI values for the entire group of patients at baseline, at week 4, at week 16, and at week 36 were 14.62, 3.02, 0.83, and 0.5, respectively. (4) Conclusions: Therapies that promote the healing of both the skin and nails in a short time can also ensure a lower risk of subsequently developing arthritis which is disabling over time. Bimekizumab proved to be particularly effective to treat NP, with a fast response in terms of complete clearance, with over 88.5% of patients free from NP after 36 weeks. The findings of our real-world study showed that patients with moderate-to-severe PsO and concomitant NP had significantly faster and more substantial improvements in NP up to 36 weeks with respect to previous research findings. Considering the rapid healing of the nail, the dual inhibition of IL17 A and F might have a great value in re-establishing the dysregulation of keratin 17 at the nail level.

Psoriasis is a common chronic inflammatory skin disease, associated with significant morbidity and a considerable negative impact on the patients' quality of life. The complex pathogenesis of psoriasis is still incompletely understood. Genetic predisposition, environmental factors like smoking, alcohol consumption, psychological stress, consumption of certain drugs, and mechanical trauma, as well as specific immune dysfunctions, contribute to the onset of the disease. Mounting evidence indicate that skin dysbiosis plays a significant role in the development and exacerbation of psoriasis through loss of immune tolerance to commensal skin flora, an altered balance between Tregs and effector cells, and an excessive Th1 and Th17 polarization. While the implications of skin dysbiosis in psoriasis pathogenesis are only starting to be revealed, the progress in the characterization of the skin microbiome changes in psoriasis patients has opened a whole new avenue of research focusing on the modulation of the skin microbiome as an adjuvant treatment for psoriasis and as part of a long-term plan to prevent disease flares. The skin microbiome may also represent a valuable predictive marker of treatment response and may aid in the selection of the optimal personalized treatment. We present the current knowledge on the skin microbiome changes in psoriasis and the results of the studies that investigated the efficacy of the different skin microbiome modulation strategies in the management of psoriasis, and discuss the complex interaction between the host and skin commensal flora.

Psoriasis, a chronic, immune-mediated, inflammatory disease, affects 2‒3% of the population. Tyrosine kinase 2 (TYK2) mediates cytokine signaling involved in adaptive [interleukin (IL)-12, IL-23] and innate (type-I interferons) immune responses; IL-23-driven T-helper (Th)17 pathways play a key role in chronic inflammation in psoriasis. In a phase 2 trial, deucravacitinib, an oral, selective, allosteric TYK2 inhibitor, reduced IL-23/Th17 and type-I interferon pathway expression in the skin of patients with moderate to severe plaque psoriasis, reductions that were accompanied by clinical improvement of psoriatic lesions.

The aim of this study was to identify biomarkers of psoriatic disease in serum from patients enrolled in the phase 2 trial and to assess the effects of deucravacitinib on those biomarkers.

Serum biomarkers from Olink proteomics and other quantitative assays were evaluated for a pharmacodynamic response to deucravacitinib treatment and correlation with psoriasis disease activity measures.

Serum biomarkers associated with the IL-23/Th17 pathway [IL-17A, IL-17C, IL-19, IL-20, beta-defensin, and peptidase inhibitor 3 (PI3)] were upregulated in patients with psoriasis versus healthy controls. Deucravacitinib treatment reduced IL-17A (adjusted mean change from baseline at Day 85; 12 mg once daily versus placebo; -0.240 versus -0.067), IL-17C (-14.850 versus -1.664), IL-19 (-96.445 versus -8.119), IL-20 (-0.265 versus -0.064), beta-defensin (-65,025.443 versus -7553.961), and PI3 (-14.005 versus -1.360) expression. Reductions in serum biomarker expression occurred in a dose- and time-dependent manner, with significant reductions from baseline seen with deucravacitinib doses ≥ 3 mg twice daily (P ≤ 0.05). Biomarker expression correlated with disease activity measures such as Psoriasis Area and Severity Index (PASI) at baseline. Biomarker expression also correlated with PASI scores at Week 12.

IL-23/Th17 pathway expression in the serum of patients with psoriasis is an indicator of disease activity and response to deucravacitinib treatment.

NCT02931838.

Our objective was to evaluate the association of serum biomarkers with baseline psoriatic arthritis (PsA) disease activity, pharmacodynamic effects of deucravacitinib on biomarker levels, and the relationship between biomarkers and clinical responses to deucravacitinib.

The phase 2 trial (ClinicalTrials.gov identifier: NCT03881059) randomly assigned 203 patients with PsA 1:1:1 to placebo, deucravacitinib at 6 mg once daily (QD), or deucravacitinib at 12 mg QD. Serum biomarkers associated with the interleukin 23 (IL-23) pathway (IL-17A, β-defensin [BD-2], and IL-19), type I interferon pathway, inflammation, and collagen matrix turnover were measured by immunoassay. Clinical responses (≥75% improvement from baseline in the Psoriasis Area and Severity Index [PASI75] and ≥20% improvement from baseline in American College of Rheumatology criteria [ACR20] responses) were measured at week 16. Hematologic variables were also assessed.

IL-17A, BD-2, and IL-19 had a modest association with PASI scores (r = 0.4, r = 0.56, and r = 0.5, respectively) at baseline. In deucravacitinib groups, IL-17A, BD-2, IL-19, C-X-C motif ligand 9 (CXCL9), CXCL10, C-reactive protein, matrix metalloproteinase 3, and collagen type 4 degradation marker levels were significantly reduced at week 16 versus baseline (P < 0.01); higher levels of IL-23 pathway-associated biomarkers predicted higher PASI75 and ACR20 response rates in deucravacitinib-treated patients. Significantly higher PASI75 response rates were seen in patients with high baseline IL-17A (odds ratio 15.76) and BD-2 levels (odds ratio 15.41) versus low baseline IL-17A and BD-2 levels. Changes in hematologic variables that are characteristic of JAK inhibition were not observed with deucravacitinib.

Deucravacitinib significantly impacted biomarkers associated with Tyk2 signaling pathways of key inflammatory cytokines, including IL-23 and type I interferon, and those related to collagen matrix turnover. These biomarkers may predict treatment responses to deucravacitinib.

Psoriasis is a chronic inflammatory skin disease with unmet needs for tailored treatment and therapy de-escalation strategies.

To evaluate early intervention with and prolonging the dosing interval for guselkumab, a p19 subunit-targeted interleukin (IL)-23 inhibitor, in patients with moderate to severe psoriasis.

The GUIDE clinical trial is an ongoing phase 3b, randomized, double-blinded trial conducted across 80 centers in Germany and France comprising 3 parts evaluating the impact of early disease intervention, prolonged dosing interval, and maintenance of response following treatment withdrawal among adults with moderate to severe plaque psoriasis. In study part 2, reported herein, first and last patient visits were September 2019 and March 2022, respectively.

In GUIDE part 1 (week [W]0-W28), patients received guselkumab, 100 mg, at W0, W4, W12, and W20. Those achieving a Psoriasis Area and Severity Index (PASI) of 0 at both W20 and W28 were termed super responders (SRes). In part 2 (W28-W68), SRes were randomized to guselkumab, 100 mg, every 8 weeks or every 16 weeks; non-SRes continued open-label guselkumab every 8 weeks.

Primary objective was to demonstrate noninferiority (with a 10% margin) of guselkumab every 16 weeks vs every 8 weeks dosing among SRes for maintenance of disease control (PASI <3 at W68). Biomarker substudies assessed immunologic effects in skin and blood.

Overall, 822 patients received guselkumab in part 2 (297 [36.1%] SRes [every 8 weeks/every 16 weeks; n = 148/n = 149] and 525 [63.9%] non-SRes). Among SRes, mean (SD) age was 39.4 (14.1) years, 95 (32.0%) were female, and 202 (68.0%) were male. The primary end point of noninferiority for guselkumab every 16 weeks vs every 8 weeks in SRes was met (P = .001), with 91.9% (137/149; 90% CI, 87.3%-95.3%) of SRes receiving every 16 weeks and 92.6% (137/148; 90% CI, 88.0%-95.8%) of SRes receiving dosing every 8 weeks having PASI lower than 3 at W68. Clinical effects corresponded with immunologic changes; skin CD8-positive tissue-resident memory T (TRM)-cell count decreased quickly from baseline, remaining low in both dosing groups. Similarly, serum IL-17A, IL-17F, IL-22, and β defensin (BD)-2 levels decreased significantly from baseline, remaining low in both dosing groups to W68. Guselkumab was well-tolerated; no new safety signals were identified.

Psoriasis treatment guidelines lack or provide inconsistent advice on patient stratification and treatment de-escalation. We present the first randomized trial providing evidence that, in patients with early complete skin clearance at 2 consecutive visits (W20 and W28), extending the guselkumab dosing interval may control disease activity.

ClinicalTrials.gov Identifier: NCT03818035.

Primary membranous nephropathy (PMN), an autoimmune disease, is the most common cause of nephrotic syndrome in middle-aged non-diabetic adults. PMN pathophysiology includes Th1/Th2 paradigm. The IL-23/IL-17 pathway is implicated in autoimmune kidney disorders, but no study has examined its relationship with PMN. In several unrelated studies, PMN patients reported to have paradoxical IL-17 levels. This manuscript describes the best possible association of IL-23/IL-17 axis with PMN. Biopsy-proven PMN patients and age, gender-matched healthy controls were enrolled. Serum-PLA2R (Euroimmune, Germany), IL-23 and IL-17 (R&D; USA), was measured using ELISA along with biochemical parameters. Appropriate statistical tools were used for analysis. One hundred eighty-nine PMN patients (mean age 41.70 ± 12.53 years) and 100 controls (mean age 43.92 ± 10.93 years) were identified. One hundred forty were PLA2R-related. PMN patients had median proteinuria, serum albumin, and creatinine of 6.12 (3.875, 9.23) g/day, 2.32 (1.96, 2.9) g/dl, and 0.89 (0.7, 1.1) mg/dl, respectively. IL-17, but not IL-23, was significantly increased in PMN patients compared to controls (IL-17, median: 12.07 pg/ml (9.75, 24.56) vs median: 9.75 pg/ml (8.23, 17.03) p = 0.0002); (IL23, median: 6.04 pg/ml (4.22, 10.82) vs median: 5.46 pg/ml (3.34, 9.96) p = 0.142). IL-17 and IL-23 correlated significantly (p 0.05) in PMN patients, and similar trend was seen when grouped into PLA2R-related and -unrelated groups. The levels of IL-23 (p = 0.057) and IL-17 (p = 0.004) were high in MN patients that did not respond to the treatment. The current finding may indicate or suggest the involvement of IL-23/IL-17 PMN pathogenesis. A comprehensive investigation is needed to evaluate IL-23/IL-17 axis with renal infiltrating immune cells, and external stimuli.

Psoriasis is a noncontagious auto-inflammatory chronic skin disease. So far, some of the inflammatory genes were upregulated in mouse model of psoriasis. This study examined changes in skin mRNA expression of L-kynureninase (Kynu), cathelicidin antimicrobial peptide (Camp), beta-defensin 2 (Defb2), and proenkephalin (Penk) in a mouse model of imiquimod-induced psoriasis.

Tree groups of C57BL/6 female mice were allocated. The imiquimod (IMQ) cream was administered to the mice dorsal skin of the two groups to induce psoriatic inflammation. In the treatment group, IMQ was administered 10 min after hydrogel-containing M7 anti-IL-17A aptamer treatment. Vaseline (Vas) was administered to the negative control group. The psoriatic skin lesions were evaluated based on the psoriasis area severity index (PASI) score, histopathology, and mRNA expression levels of Kynu, Camp, Defb2, and Penk using real-time PCR. In order to assess the systemic response, the spleen and lymph node indexes were also evaluated.

The PASI and epidermal thickness scores were 6.01 and 1.96, respectively, in the IMQ group, and they significantly decreased after aptamer administration to 1.15 and 0.90, respectively (P < 0.05). Spleen and lymph node indexes showed an increase in the IMQ group, followed by a slight decrease after aptamer treatment (P > 0.05). Additionally, the mRNA expression levels of Kynu, Defb2, Camp, and Penk genes in the IMQ-treated region showed a significant 2.70, 4.56, 3.29, and 2.61-fold increase relative to the Vas mice, respectively (P < 0.05). The aptamer-treated region exhibited a significant decrease in these gene expression levels (P < 0.05). A positive correlation was found between Kynu, Penk, and Camp expression levels and erythema, as well as Camp expression with PASI, scaling, and thickness (P < 0.05).

According to our results, it seems that Kynu, Camp, and Penk can be considered appropriate markers for the evaluation of psoriasis in IMQ-induced psoriasis. Also, the anti-IL-17 aptamer downregulated these important genes in this mouse model.

Psoriasis is a multifactorial disease that affects 0.84% of the global population and it can be associated with disabling comorbidities. As patients present with thick scaly lesions, psoriasis was long believed to be a disorder of keratinocytes. Psoriasis is now understood to be the outcome of the interaction between immunological and environmental factors in individuals with genetic predisposition. While it was initially thought to be solely mediated by cytokines of type-1 immunity, namely interferon-γ, interleukin-2, and interleukin-12 because it responds very well to cyclosporine, a reversible IL-2 inhibitor; the discovery of Th-17 cells advanced the understanding of the disease and helped the development of biological therapy. This article aims to provide a comprehensive review of the role of cytokines in psoriasis, highlighting areas of controversy and identifying the connection between cytokine imbalance and disease manifestations. It also presents the approved targeted treatments for psoriasis and those currently under investigation.

Psoriasis is an inflammatory skin disease characterized by epidermal and immune dysfunctions. Although efficient, current topical treatments display adverse effects, including skin atrophy and burning sensation, leading to poor patient adherence. To overcome these downsides, pickering emulsions were formulated in which the calcitriol-containing dispersed phase was stabilized with either cyclosporin A- or tacrolimus-loaded poly(lactic-co-glycolic) acid nanoparticles. This study aimed to investigate their biological effects on lymphocytes and epidermal cells and their effectiveness in an imiquimod-induced psoriasis-like mouse model. Results showed that both emulsions significantly inhibited nuclear factor of activated T cell translocation in T lymphocytes as well as their IL-2 production, cell activation, and proliferation. In keratinocytes, inhibition of nuclear factor of activated T cell translocation decreased the production of IL-8 and TNF-α. Topical application of emulsions over skin biopsies ex vivo showed accumulation of rhodamin B-coupled poly(lactic-co-glycolic) acid nanoparticles throughout the epidermis by immunofluorescence and significantly decreased the antigen-presenting capacity of Langerhans cells in relation to a reduced expression of activation markers CD40, CD86, and HLA-DR. Using an imiquimod-induced psoriasis model in vivo, pickering emulsions significantly alleviated psoriasiform lesions potentially attributed to the decreased cutaneous expression of T-cell markers, proinflammatory cytokines, chemokines, and specific epidermal cell genes. Altogether, pickering emulsion might be a very efficient formulation for treating inflammatory dermatoses.

The skin is a complex and dynamic organ where homeostasis is maintained through the intricate interplay between the immune system and metabolism, particularly cholesterol metabolism. Various factors such as cytokines, inflammatory mediators, cholesterol metabolites, and metabolic enzymes play crucial roles in facilitating these interactions. Dysregulation of this delicate balance contributes to the pathogenic pathways of inflammatory skin conditions, notably psoriasis. In this article, we provide an overview of omics biomarkers associated with psoriasis in relation to cholesterol metabolism. We explore multi-omics approaches that reveal the communication between immunometabolism and psoriatic inflammation. Additionally, we summarize the use of multi-omics strategies to uncover the complexities of multifactorial and heterogeneous inflammatory diseases. Finally, we highlight potential future perspectives related to targeted drug therapies and research areas that can advance precise medicine. This review aims to serve as a valuable resource for those investigating the role of cholesterol metabolism in psoriasis.

We assessed and compared immunologic differences and associations with clinical response to guselkumab, a fully human interleukin (IL)-23p19 subunit inhibitor, in participants with active psoriatic arthritis (PsA) who were biologic-naive or had inadequate response to tumor necrosis factor inhibitors (TNFi-IR).

Serum biomarker levels at baseline and after treatment with guselkumab 100 mg every 8 weeks were compared between biologic-naive (n = 251) and TNFi-IR (n = 93) subgroups identified in the pooled DISCOVER-1/DISCOVER-2/COSMOS data set. Baseline biomarker levels determined by achievement of week 24 clinical responses (≥75%/90% improvement in Psoriasis Area and Severity Index [PASI 75/90], Investigator's Global Assessment [IGA] of psoriasis score 0/1 and ≥2-point improvement], ≥20% improvement in American College of Rheumatology criteria [ACR20]) were compared between prior treatment subgroups.

Baseline IL-22, TNFα, and beta defensin-2 (BD-2) levels were significantly lower in biologic-naive than in TNFi-IR participants. With guselkumab, week 24 IL-17A, IL-17F, IL-22, serum amyloid A, C-reactive protein, IL-6, and BD-2 levels were significantly reduced from baseline in biologic-naive and TNFi-IR participants (≥1.4-fold difference, nominal P < 0.05). Clinical responders to guselkumab exhibited significantly higher baseline levels of several biomarkers than nonresponders (IL-17A, IL-17F, BD-2 in biologic-naive PASI 90 responders; IL-17A, BD-2 in TNFi-IR IGA 0/1 responders; IL-22, BD-2 in TNFi-IR PASI 90 responders [nominal P < 0.05]) and trended higher in TNFi-IR ACR20 responders.

Guselkumab modulates IL-23 signaling and provides consistent pharmacodynamic effects in both biologic-naive and TNFi-IR PsA patients. Significantly elevated baseline IL-22, TNFα, and BD-2 levels and associations between baseline IL-22, IL-17A, and BD-2 levels and skin responses to guselkumab suggest greater dysregulation of IL-23/Th17 signaling in patients with TNFi-IR.

Cedirogant (ABBV-157) is an orally bioavailable inverse agonist of retinoic acid-related orphan receptor gamma thymus. Data from 2 Phase 1 studies were used to characterize cedirogant pharmacokinetics and evaluate target engagement. Cedirogant plasma concentrations and ex vivo interleukin 17A (IL-17A) concentrations from healthy participants and participants with moderate to severe psoriasis (PsO) were analyzed in a population pharmacokinetic and pharmacodynamic modeling framework to characterize cedirogant pharmacokinetics following single and multiple doses and assess ex vivo IL-17A inhibition in relation to cedirogant exposure. Cedirogant population pharmacokinetics were best described by a 2-compartment pharmacokinetic model with delayed absorption and an enzyme turnover compartment to describe cytochrome P450 3A autoinduction. The pharmacokinetics of cedirogant were comparable between healthy participants and participants with PsO. Cedirogant steady-state average and maximum plasma concentrations were predicted to be 7.56 and 11.8 mg/L, respectively, for participants with PsO for the 375 mg once-daily regimen on Day 14. The apparent clearance and apparent volume of distribution for cedirogant were estimated to be 24.5 L/day and 28.2 L, respectively. A direct maximum inhibition model adequately characterized the exposure-response relationship of cedirogant and ex vivo IL-17A inhibition, indicating no temporal delay between exposure and response with a saturable inhibition of IL-17A. Model-estimated half-maximal inhibitory concentration and maximum inhibition values for cedirogant inhibition of ex vivo IL-17A were 0.56 mg/L and 0.76, respectively. The established relationship between cedirogant exposure and biomarker effect supported dose selection for the Phase 2 dose-ranging study in patients with PsO.

Alarmins are immune-activating factors released after cellular injury or death. By secreting alarmins, cells can interact with immune cells and induce a variety of inflammatory responses. The broad family of alarmins involves several members, such as high-mobility group box 1, S100 proteins, interleukin-33, and heat shock proteins, among others. Studies have found that the concentrations and expression profiles of alarmins are altered in immune-mediated diseases. Furthermore, they are involved in the pathogenesis of inflammatory conditions. The aim of this narrative review is to present the current evidence on the role of alarmins in rheumatoid arthritis, osteoarthritis, and psoriasis. We discuss their potential involvement in mechanisms underlying the progression of these diseases and whether they could become therapeutic targets. Moreover, we summarize the impact of pharmacological agents used in the treatment of these diseases on the expression of alarmins.

Background/Objectives: Treating psoriasis patients requires the consideration of potential underlying complications like latent viral infections and chronic kidney disease, which may influence therapy selection. Case presentation: A patient with end-stage kidney disease (ESKD) undergoing hemodialysis (HD) was successfully treated with bimekizumab, an IgG1 humanized monoclonal antibody inhibiting interleukin (IL)-17A and IL-17F. This case appears to be the first documented instance of effective anti-IL-17A/IL-17F antibody treatment in a psoriasis patient undergoing HD, with a sustained positive response for eight months. Discussion: Studies indicate the comparable pharmacokinetics, efficacy, and safety of certain psoriasis drugs in patients with chronic kidney disease (CKD) and those with normal renal function. The positive clinical outcome observed following treatment with bimekizumab aligns with the existing literature on this topic. However, further studies are needed to objectively evaluate the pharmacokinetics, efficacy, and safety of this drug in this specific setting. Conclusions: This documented case represents the first known use of bimekizumab to treat psoriasis in patients undergoing dialysis, suggesting its potential effectiveness and safety in this population.

Beta-defensins (BDs) are antimicrobial peptides secreted upon epithelial injury. Both chemotactic and antimicrobial properties of BDs function as initial steps in host defense and prime the adaptive immune system in the body. Psoriasis, a chronic immune-mediated inflammatory disease, has both visible cutaneous manifestations as well as known associations with higher incidence of cardiometabolic complications and vascular inflammation.

We aimed to investigate the circulating expression of beta-defensin-2 (BD2) in psoriasis at baseline compared to control subjects, along with changes in BD2 levels following biologic treatment at one-year. The contribution of BD2 to subclinical atherosclerosis is also assessed. In addition, we have sought to unravel signaling mechanisms linking inflammation with BD2 expression.

Multimodality imaging as well inflammatory biomarker assays were performed in biologic naïve psoriasis (n=71) and non-psoriasis (n=53) subjects. A subset of psoriasis patients were followed for one-year after biological intervention (anti-Tumor Necrosis Factor-α (TNFα), n=30; anti-Interleukin17A (IL17A), n=21). Measurements of circulating BD2 were completed by Enzyme-Linked Immunosorbent Assay (ELISA). Using HaCaT transformed keratinocytes, expression of BD2 upon cytokine treatment was assessed by quantitative polymerase chain reaction (qPCR) and ELISA.

Herein, we confirm that human circulating BD2 levels associate with psoriasis, which attenuate upon biologic interventions (anti-TNFα, anti-IL-17A). A link between circulating BD2 and sub-clinical atherosclerosis markers was not observed. Furthermore, we demonstrate that IL-17A-driven BD2 expression occurs in a Phosphatidylinositol 3-kinase (PI3-kinase) and Rac1 GTPase-dependent manner.

Our findings expand on the potential role of BD2 as a tractable biomarker in psoriasis patients and describes the role of an IL-17A-PI3-kinase/Rac signaling axis in regulating BD2 levels in keratinocytes.

Targeting of the proinflammatory cytokine interleukin 17A (IL-17A) or tumor necrosis factor alpha (TNFα) with the monoclonal antibodies (mAbs) ixekizumab or adalimumab, respectively, is a successful therapy for chronic plaque psoriasis. The effects of these treatments on immune cell populations in the skin are largely unknown.

In this study, we compared the composition of cutaneous, lesional and non-lesional immune cells and blood immune cells in ixekizumab- or adalimumab-treated patients with psoriasis.

Our data reveal that both treatments efficiently downregulate T cells, macrophages and different subsets of dendritic cells (DCs) in lesional skin towards levels of healthy skin. In contrast to lesional skin, non-lesional areas in patients harbor only few or no detectable DCs compared to the skin of healthy subjects. Treatment with neither ixekizumab nor adalimumab reversed this DC imbalance in non-lesional skin of psoriatic patients.

Our study shows that anti-IL-17A and anti-TNFα therapy rebalances the immune cell repertoire of lesional skin in psoriatic patients but fails to restore the disturbed immune cell repertoire in non-lesional skin.

Little is known about IL-17 expression in psoriasis and the actual cellular source of IL-17 remains incompletely defined. We show that high numbers of IL-17 + mast cells persisted in resolved lesions after treatment (anti-IL-17A, anti-IL-23, UVB or topical dithranol) and correlated inversely with the time span in remission. IL-17 + mast cells were found in T cell-rich areas and often close to resident memory T cells (Trm) in active psoriasis and resolved lesional skin. Digital cytometry by deconvolution of RNA-seq data showed that activated mast cells were increased in psoriatic skin, while resting mast cells were almost absent and both returned to normal levels after treatment. When primary human skin mast cells were stimulated with T cell cytokines (TNFα, IL-22 and IFNγ), they responded by releasing more IL-17A, as measured by ELISA. In situ mRNA detection using padlock probes specific for transcript variants of IL17A, IL17F, and RORC (encoding the Th17 transcription factor RORγt) revealed positive mRNA signals for IL17A, IL17F, and RORCin tryptase + cells, demonstrating that mast cells have the transcriptional machinery to actively produce IL-17. Mast cells thus belong to the center of the IL-23/IL-17 axis and high numbers of IL-17 + mast cells predict an earlier disease recurrence.

The use of monoclonal antibodies has changed the treatment of several immune-mediated inflammatory diseases, including psoriasis. However, these large proteins must be administered by injection. JNJ-77242113 is a novel, orally administered interleukin-23-receptor antagonist peptide that selectively blocks interleukin-23 signaling and downstream cytokine production.

In this phase 2 dose-finding trial, we randomly assigned patients with moderate-to-severe plaque psoriasis to receive JNJ-77242113 at a dose of 25 mg once daily, 25 mg twice daily, 50 mg once daily, 100 mg once daily, or 100 mg twice daily or placebo for 16 weeks. The primary end point was a reduction from baseline of at least 75% in the Psoriasis Area and Severity Index (PASI) score (PASI 75 response; PASI scores range from 0 to 72, with higher scores indicating greater extent or severity of psoriasis) at week 16.

A total of 255 patients underwent randomization. The mean PASI score at baseline was 19.1. The mean duration of psoriasis was 18.2 years, and 78% of the patients across all the trial groups had previously received systemic treatments. At week 16, the percentages of patients with a PASI 75 response were higher among those in the JNJ-77242113 groups (37%, 51%, 58%, 65%, and 79% in the 25-mg once-daily, 25-mg twice-daily, 50-mg once-daily, 100-mg once-daily, and 100-mg twice-daily groups, respectively) than among those in the placebo group (9%), a finding that showed a significant dose-response relationship (P<0.001). The most common adverse events included coronavirus disease 2019 (in 12% of the patients in the placebo group and in 11% of those across the JNJ-77242113 dose groups) and nasopharyngitis (in 5% and 7%, respectively). The percentages of patients who had at least one adverse event were similar in the combined JNJ-77242113 dose group (52%) and the placebo group (51%). There was no evidence of a dose-related increase in adverse events across the JNJ-77242113 dose groups.

After 16 weeks of once- or twice-daily oral administration, treatment with the interleukin-23-receptor antagonist peptide JNJ-77242113 showed greater efficacy than placebo in patients with moderate-to-severe plaque psoriasis. (Funded by Janssen Research and Development; FRONTIER 1 ClinicalTrials.gov number, NCT05223868.).

Most of the government regulatory agencies, including the United States Food and Drug Administration and the European Medicine Agency, demand that the generic complex topical products prove pharmaceutical and bioequivalence. The evaluation of bioequivalence for complex topical dermatological formulations is a challenging task that requires careful consideration of several factors. Although comparative clinical studies are still considered the gold standard approach for establishing bioequivalence in most formulations, these studies can be costly and insensitive to detect formulation differences. Therefore, significant efforts have been made to develop and validate alternative approaches that demonstrate bioequivalence and expedite the availability of high-quality generic topical dermatological products. This article reviews the current methods for determining the bioequivalence of topical formulations in humans, with particular emphasis on recent advances in these methodologies. Most of the alternative methods are sensitive and reproducible, with the capability to ease the financial burden of comparative clinical studies within a short delivery time. The limitations associated with each technique are reviewed in detail.